CD8 positive cytotoxic T lymphocytes (CTLs) have been shown to recognize epitope peptides derived from the tumor-associated antigens (TAAs) found on the major histocompatibility complex (MHC) class I molecule, and then kill the tumor cells. Since the discovery of the melanoma antigen (MAGE) family as the first example of TAAs, many other TAAs have been discovered, primarily through immunological approaches (NPL 1-2). Some of these TAAs are currently undergoing clinical development as immunotherapeutic targets.
Favorable TAAs are indispensable for the proliferation and survival of cancer cells. The use of such TAAs as targets for immunotherapy may minimize the well-described risk of immune escape of cancer cells attributable to deletion, mutation, or downregulation of TAAs as a consequence of therapeutically driven immune selection. Accordingly, the identification of new TAAs capable of inducing potent and specific anti-tumor immune responses warrants further development. Thus, the clinical application of peptide vaccination strategies for various types of cancer is ongoing (NPL 3-10). To date, there have been several reports of clinical trials using these TAA derived peptides. Unfortunately, these cancer vaccine trials have to date yielded only a low objective response rate (NPL 11-13). Accordingly, there remains a need for new TAAs as immunotherapeutic targets.
KNTC2, also known as “kinetchore associated 2”, HEC1 or NDC 80, is a member of the Ndc80 complex that is composed of the two subcomplexes of Ndc80 (KNTC2)-Nuf2 (CDCA1) and Spc24-Spc25 (NPL 14). The attachment sites of the CDCA1-KNTC2 complex within the kinetochore outer plate generate microtubule dependent forces for chromosomal movement and regulate spindle checkpoint protein assembly at the kinetochore (NPL 15).
In the course of clarifying the molecular mechanism in non-small cell lung cancer (NSCLC) by genome-wide expression profile analysis using cDNA microarray containing 27,648 genes, KNTC2 was discovered to be frequently over expressed in NSCLC (NPL 16, 17, 18, 19, 20). Northern blot analyses revealed this gene transcript to be highly expressed in lung cancer tissues but not expressed in normal tissues, with the exception of the testis. Moreover, subsequent knockdown of KNTC2 expression with siRNA was shown to significantly suppress growth of NSCLC cells (NPL 21, PTL 1).
KNTC2 has also been reported to be up-regulated in tissues of cancers, such as bladder cancer, breast cancer, cervical cancer, cholangiocellular carcinoma, chronic myeloid leukemia (CML), colorectal cancer, esophageal cancer, non-small cell lung cancer (NSCLC), lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, small cell lung cancer (SCLC) and soft tissue tumor (PTL 2).
In addition, the present inventors have identified a KNTC2 peptide that can bind to HLA-A24 and induce CTLs, and that is useful for an immunotherapy that targets HLA-A24 positive patients (PTL 2). However, although these peptides may be suitable for patients expressing the HLA-A24 subtype, there remains a need for peptides that induce CTL in patients expressing other types of HLA antigen.